Still a reasonable goal: Targeting cholesterol in dialysis and advanced chronic kidney disease patients.

Chronic kidney disease (CKD) patients have a high burden of cardiovascular disease. In the general population, lipid metabolism disorders, which cause the initiation and progression of atherosclerotic vascular changes, are major targets for preventive and therapeutic strategies in cardiovascular medicine. However, data from large cohort studies and from clinical trials suggest that the treatment guidelines on cardiovascular disease prevention and therapy cannot uncritically be transferred from individuals with intact renal function to CKD patients. Thus, unlike in the general population, neither plasma levels of HDL-cholesterol, nor the key parameter of HDL-cholesterol function-that is, cholesterol efflux capacity-predicts future cardiovascular events. Therefore, HDL-cholesterol should presently not be considered as therapeutic target in CKD patients. In contrast, lowering of LDL-cholesterol has been shown to reduce cardiovascular events at least among nondialysis CKD patients. The cardiovascular benefit of targeting LDL-cholesterol among dialysis CKD patients is less evident. We strongly believe that at least some subgroups of dialysis patients may profit from such treatment, particularly those with highest baseline LDL-cholesterol. Finally, as CKD patients have been characterized to have rather high intestinal cholesterol absorption, and relatively low hepatic cholesterol synthesis, substituting combined statin/ezetimibe treatment for statin monotherapy may be of particular benefit for nephrologic patients.

Best Albuminuria Measurement to Predict Cardiovascular and Renal Events.

BACKGROUND: Kidney Disease Improving Global Outcomes (KDIGO) guidelines encourage clinicians to estimate 24-hour albuminuria as albumin to creatinine ratio (ACR) from spot urine samples. However, ACR underestimates 24-hour albumin excretion in muscular individuals. Equations that adjust ACR for surrogates of muscle mass to yield an estimated albumin excretion rate (eAER) were developed. We hypothesised that eAER is a better predictor of cardiovascular and renal outcomes than ACR. METHODS: We determined ACR and eAER among 443 patients with chronic kidney disease G2-G4 recruited into the CARE FOR HOMe study. Patients were classified into KDIGO albuminuria categories, and followed for cardiovascular and renal events. The primary analysis was the net reclassification improvement (NRI) for those with and without events within 3 years of follow-up. RESULTS: Eighty five patients experienced cardiovascular events during 3 years of follow-up, 13 of whom were reclassified to a more advanced albuminuria category, and 1 patient to a less advanced category by eAER compared to ACR (NRIevent: 14.1% (95% CI 5.8-22.4)). Among 358 patients without a cardiovascular event, 17 patients were reclassified to a more advanced albuminuria category, and 2 patients to a less advanced category by eAER (NRIno event: -4.2%, 95% CI -8.5 to -1.8). Sixty patients went through renal events, and 383 patients had event-free 3-year follow-up. NRIevent was 6.7% (95% CI -1.2 to 14.5), and NRIno event was -6.0% (95% CI -10.6 to 3.4) for renal events. CONCLUSION: Compared to ACR albuminuria categories, eAER categories are better associated with future cardiovascular events, but not with renal events.

Comparison of two different strategies for human monocyte subsets gating within the large-scale prospective CARE FOR HOMe Study.

Monocytes are heterogeneous cells consisting of (at least) three subsets: classical, intermediate, and nonclassical monocytes. Correct enumeration of cell counts necessitates well-defined gating strategies, which are essentially based upon CD14 and CD16 expression. For the delineation of intermediate from nonclassical monocytes, a "rectangular gating (RG) strategy" and a "trapezoid gating (TG) strategy" have been proposed. We compared the two gating strategies in a well-defined clinical cohort of patients with chronic kidney disease (CKD). Within the ongoing CARE FOR HOMe study, monocyte subsets were reanalyzed in 416 CKD patients, who were followed 3.6 ± 1.6 years for the occurrence of a cardiovascular event. Gating was performed by either RG or TG. We analyzed the expression of surface markers, and compared the predictive role of cell counts of monocyte subsets, as defined by RG and TG, respectively. With both gating strategies, higher intermediate monocyte counts predicted the cardiovascular endpoint in Kaplan-Meier analyses (P < 0.001 with RG; P < 0.001 with TG). After correction for confounders, intermediate monocyte counts remained independent predictors in Cox-Regression analyses (HR = 1.013 [95% CI: 1.006-1.020; P < 0.001] with RG; HR = 1.015 [95% CI: 1.006-1.024; P = 0.001] with TG). NRI was 3.9% when reclassifying patients from quartiles of intermediate monocyte counts with RG strategy toward quartiles of intermediate monocytes counts with TG strategy. In expression analysis, those monocytes which are defined as intermediate monocytes by the RG strategy and as nonclassical monocytes by the TG strategy share characteristics of both subsets. In conclusion, intermediate monocytes were independent predictors of cardiovascular outcome irrespective of the applied gating strategy. Future studies should aim to identify markers that allow for an unequivocal definition of intermediate monocytes, which may further improve their power to predict cardiovascular events.

Immunosuppression and monocyte subsets.

BACKGROUND: Monocytes are critical in innate immunity and transplantation. Three monocyte subsets exist, CD14(++)CD16(-), CD14(++)CD16(+) and CD14(+)CD16(++) monocytes; cell counts of CD14(++)CD16(+) and CD14(+)CD16(++) monocytes are increased in pre-transplant chronic kidney disease. Interestingly, the effect of immunosuppressants on monocyte heterogeneity has not been well studied. METHODS: The impact of immunosuppressants on monocyte subsets was studied: (i) in 152 kidney transplant (KTx) recipients to characterize subset distribution in the steady state, (ii) in patients after autologous (n = 10) versus allogenic (n = 9) haematopoietic stem cell transplantation (HSCT) to analyse monocyte subset development and (iii) in an in vitro model to compare the effect of immunosuppressants on monocyte subset biology. RESULTS: In KTx, steroid intake was associated with higher total, CD14(++)CD16(-) and CD14(++)CD16(+) monocyte counts, but fewer CD14(+)CD16(++) monocytes, whereas intake of mycophenolate, calcineurin inhibitors (CNI) and mammalian target of rapamycin inhibitors (mTORI) did not affect monocyte (subset) counts. In linear regression analysis, only steroid intake was a significant determinant of monocyte (subset) counts: total monocytes (ß = 0.331; P < 0.001), CD14(++)CD16(-) monocytes (ß = 0.374; P < 0.001), CD14(++)CD16(+) monocytes (ß = 0.221; P = 0.010) and CD14(+)CD16(++) monocytes (ß = -0.169; P = 0.049). After HSCT, CD14(++)CD16(-) monocytes were the first to arise, followed by CD14(++)CD16(+) and later by CD14(+)CD16(++) monocytes. Monocyte subset distribution did not differ significantly in patients after allogenic compared with autologous transplantation. CNI, mycophenolate and methotrexate did not influence monocyte subset development, but modified surface receptor expression (CCR2, HLA-DR, ENG, TEK and TLR4) in allogenic HSCT. CONCLUSION: Chronic low-dose steroids are associated with monocytosis and higher counts of CD14(++)CD16(-) and of proinflammatory CD14(++)CD16(+) monocytes.

Lower Apo A-I and lower HDL-C levels are associated with higher intermediate CD14++CD16+ monocyte counts that predict cardiovascular events in chronic kidney disease.

OBJECTIVE: Patients with chronic kidney disease (CKD) display impaired cholesterol efflux capacity and elevated CD14(++)CD16(+) monocyte counts. In mice, dysfunctional cholesterol efflux causes monocytosis. It is unknown whether cholesterol efflux capacity and monocyte subsets are associated in CKD. APPROACH AND RESULTS: In 438 patients with CKD, mediators of cholesterol efflux capacity (high-density lipoprotein cholesterol/apolipoprotein A-I) and monocyte subsets were analyzed as predictors of cardiovascular events. Monocyte subset-specific intracellular lipid content, CD36, CD68, and ABCA1 were measured in a subgroup. Experimentally, we analyzed subset-specific cholesterol efflux capacity and response to oxidized low-density lipoprotein cholesterol stimulation in CKD. Epidemiologically, both low Apo-I and low high-density lipoprotein cholesterol were associated with high CD14(++)CD16(+) monocyte counts in linear regression analyses (apolipoprotein A-I: ß=-0.171; P<0.001; high-density lipoprotein cholesterol: ß=-0.138; P=0.005), but not with counts of other monocyte subsets. In contrast to apolipoprotein A-I or high-density lipoprotein cholesterol, higher CD14(++)CD16(+) monocyte counts independently predicted cardiovascular events (hazard ratio per increase of 1 cell/µL: 1.011 [1.003-1.020]; P=0.007). Experimentally, CD14(++)CD16(+) monocytes demonstrated preferential lipid accumulation, high CD36, CD68, and low ABCA1 expression and, consequently, displayed low cholesterol efflux capacity, avid oxidized low-density lipoprotein cholesterol uptake, and potent intracellular interleukin-6, interleukin-1ß, and tumor necrosis factor-α production. CONCLUSIONS: Taken together, mediators of cholesterol efflux are associated with CD14(++)CD16(+) monocyte counts, which independently predict adverse outcome in CKD.

Distinct immunologic effects of different intravenous iron preparations on monocytes.

BACKGROUND: Iron deficiency contributes to anaemia in patients with chronic kidney disease. I.v. iron is therefore widely used for anaemia treatment, although it may induce oxidative stress and activate monocytes. Different i.v. iron preparations are available, but interestingly their substance-specific immunologic effects are poorly studied. METHODS: We analysed the effect of iron sucrose, ferric carboxymaltose, iron isomaltoside 1000, low-molecular-weight iron dextran and ferumoxytol on classical, intermediate and nonclassical monocyte biology. We therefore stimulated in vitro mature monocytes and haematopoietic CD34(+) stem cells during their differentiation into monocytes with different concentrations (0.133, 0.266, 0.533 mg/mL) of i.v. iron preparations. Alterations of monocyte subset distribution, expression of surface markers (CD86, CCR5, CX3CR1), as well as production of pro-inflammatory cytokines (TNF-α, IL-1ß) and reactive oxygen species were measured using flow cytometry. Additionally, we analysed phagocytosis and antigen presentation capacity. RESULTS: We found specific immunologic effects after stimulation with iron sucrose which were not induced by the other iron preparations. Iron sucrose activated monocyte subsets leading to significantly increased CD86 expression. Simultaneously CD16 and CX3CR1 expression and monocytic phagocytosis capacity were decreased. Additionally, differentiation of monocytes from haematopoietic CD34(+) stem cells was almost completely abolished after stimulation with iron sucrose. CONCLUSIONS: Our findings demonstrate that specific immunologic effects of distinct i.v. iron preparations exist. The clinical relevance of these findings requires further investigation.

The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation incorporating both cystatin C and creatinine best predicts individual risk: a cohort study in 444 patients with chronic kidney disease.

BACKGROUND: The recently introduced CKD-EPIcreat-cys equation surpassed creatinine-based equations for GFR estimation in a large cross-sectional analysis. However, its performance to predict individual risk of CKD progression and death in patients with various underlying CKD etiologies is unknown. METHODS: We recruited 444 patients with CKD GFR categories 2-4 (eGFR 15-89 mL/min/1.73 m2); baseline eGFR was estimated by the established MDRD and CKD-EPIcreat equations and by the novel CKD-EPIcreat-cys equation. RESULTS: Patients were followed for 2.7±1.2 years for the occurrence of the combined predefined endpoint event: death, need for renal replacement therapy or halving of eGFR. The endpoint occurred in 62 patients. Reclassification from MDRD determined categories to CKD-EPIcreat-cys categories yielded net reclassification improvements for those with the endpoint event (NRIevents) of 27.4% (95% CI: 16.7-40.0%) and for those without the event (NRInon-events) of -3.1% (-8.2 to 1.6%). Similarly, reclassification from CKD-EPIcreat categories to CKD-EPIcreat-cys categories yielded an NRIevents of 22.6% (10.2-34.3%) and NRInon-events of -11.3% (-15.9 to -6.5%). Addition of albuminuria to each eGFR equation increased the calculated risk of the outcome for a net 26-32% of those who subsequently reached the endpoint, and reduced the calculated risk in a net 21-23% in non-event patients, but only minimally. CONCLUSIONS: The CKD-EPIcreat-cys equation assigned patients who went on to have the event to more appropriate CKD risk categories than MDRD and CKD-EPIcreat, but patients without the event to less appropriate categories than CKD-EPIcreat. Addition of albuminuria marginally improved risk classification for those who had the event.

SuperSAGE evidence for CD14++CD16+ monocytes as a third monocyte subset.

Monocytes are a heterogeneous cell population with subset-specific functions and phenotypes. The differential expression of CD14 and CD16 distinguishes classical CD14(++)CD16(-), intermediate CD14(++)CD16(+), and nonclassical CD14(+)CD16(++) monocytes. Current knowledge on human monocyte heterogeneity is still incomplete: while it is increasingly acknowledged that CD14(++)CD16(+) monocytes are of outstanding significance in 2 global health issues, namely HIV-1 infection and atherosclerosis, CD14(++)CD16(+) monocytes remain the most poorly characterized subset so far. We therefore developed a method to purify the 3 monocyte subsets from human blood and analyzed their transcriptomes using SuperSAGE in combination with high-throughput sequencing. Analysis of 5 487 603 tags revealed unique identifiers of CD14(++)CD16(+) monocytes, delineating these cells from the 2 other monocyte subsets. Gene Ontology (GO) enrichment analysis suggests diverse immunologic functions, linking CD14(++)CD16(+) monocytes to Ag processing and presentation (eg, CD74, HLA-DR, IFI30, CTSB), to inflammation and monocyte activation (eg, TGFB1, AIF1, PTPN6), and to angiogenesis (eg, TIE2, CD105). In conclusion, we provide genetic evidence for a distinct role of CD14(++)CD16(+) monocytes in human immunity. After CD14(++)CD16(+) monocytes have earlier been discussed as a potential therapeutic target in inflammatory diseases, we are hopeful that our data will spur further research in the field of monocyte heterogeneity.

Clinical relevance of epigenetic dysregulation in chronic kidney disease-associated cardiovascular disease.

Across the spectrum of clinical medicine, the field of epigenetics has gained substantial scientific interest in recent years. Epigenetics refers to modifications in gene expression which are not explained by changes in DNA sequence. Classical components of epigenetic regulation comprise DNA methylation, histone modifications and RNA interference. In chronic kidney disease (CKD), several features of uraemia, such as hyperhomocysteinemia and inflammation, may contribute to changes in epigenetic gene regulation. It has been suggested that these changes may affect genes related to cardiovascular disease. Thereby, a uraemia-associated disturbance in epigenetic regulation may contribute to the substantial increase in cardiovascular morbidity in CKD patients. The present review aims to summarize current knowledge of epigenetic dysregulation in cardiovascular disease from a nephrological perspective, with a special focus on DNA methylation. We first describe the impact of altered epigenetic regulation in non-CKD-associated arteriosclerosis, and next characterize uraemic features which may affect epigenetic gene regulation in the context of cardiovascular disease. Finally, we conclude that substantial additional work is needed before epigenetic regulatory mechanisms may become therapeutic targets in CKD-associated cardiovascular disease.

Does the measurement of the difference of resistive indexes in spleen and kidney allow a selective assessment of chronic kidney injury?

PURPOSE: To determine whether the difference of resistive indexes (RIs) in spleen and kidney (DI-RISK) is a more specific ultrasonographic (US) marker of intrarenal parenchymal damage than intrarenal RI alone. MATERIALS AND METHODS: The study was approved by the local ethics committee. All study participants provided informed consent. The authors defined standard values for renal RI, splenic RI, and DI-RISK in 152 healthy subjects; carotid intima media thickness (IMT) was assessed as a marker of systemic vascular disease. Next, the authors measured these US parameters and collected echocardiographic data in 290 patients with chronic kidney disease (stage 2-4) recruited between September 2008 and February 2011 to evaluate the DI-RISK across the spectrum of stages of kidney function. Correlation coefficients were calculated with the Spearman test, and multivariate linear regression was used to analyze independent predictors of renal RI, splenic RI, and DI-RISK. RESULTS: Healthy subjects had a mean age of 34.3 years ± 8.7, and patients with chronic kidney disease had a mean age of 65.0 years ± 12.3 (P < .001). In healthy subjects, both renal and splenic RIs were associated with IMT (renal RI: r = 0.19, P = .022; splenic RI: r = 0.23, P = .005); there was no correlation between DI-RISK and IMT (r = -0.10, P = .215). Similarly, in patients with chronic kidney disease, renal and splenic RIs correlated with IMT (renal RI: r = 0.33, P < .001; splenic RI: r = 0.30, P = .001). DI-RISK was associated with the estimated glomerular filtration rate (eGFR; r = -0.19, P = .001) but not with IMT (r = 0.08, P = .174). At multivariate regression analysis, DI-RISK was independently associated with eGFR but not with extrarenal factors. CONCLUSION: In patients with chronic kidney disease, renal RIs do not selectively indicate organ damage, but also mirror systemic vascular disease. The authors introduced DI-RISK as a potential US marker that may more specifically reflect kidney damage.

Ultrasound renal resistive index is not an organ-specific predictor of allograft outcome.

BACKGROUND: Ultrasound-measured renal resistive index (RRI) has been suggested to predict allograft survival in renal transplant recipients. Based on experimental and clinical data, we objected to the theory that RRI specifically mirrors allograft characteristics. Instead, we hypothesized that RRI rather represents a marker of systemic vascular damage than an organ-specific marker. In order to refute this hypothesis, RRI should override the resistive index measured in other abdominal parenchymatous organs-such as the spleen-as predictor of allograft outcome. We therefore set out to simultaneously measure renal and splenic ultrasound resistive index in kidney allograft recipients. METHODS: Eighty-seven stable transplant recipients were recruited. We measured RRI, splenic resistive index (SRI) and an established marker of systemic vascular damage, namely common carotid intima-media thickness (IMT). During a follow-up of 4.9 ± 0.5 years, the occurrence of the combined primary end point, defined as a decrease of ≥ 50% in estimated glomerular filtration rate (eGFR), need for dialysis treatment or death, was recorded. RESULTS: At baseline, both RRI and SRI correlated with common carotid IMT [RRI: r = 0.203 (P = 0.006); SRI: r = 0.315 (P < 0.001)], but not with allograft-specific markers such as eGFR or proteinuria. Elevated RRI was a weak non-significant predictor of the combined primary end point. Notably, RRI did not surpass SRI as outcome predictor. When analysing individual components of the combined primary end point separately, elevated RRI failed to predict strictly renal events (decrease of ≥ 50% in eGFR/need for dialysis treatment), while it predicted total mortality. CONCLUSIONS: Our findings support the notion that RRI is not a specific indicator of allograft damage. Similar to SRI, RRI is rather associated with systemic vascular damage markers and mortality.

CD14++CD16+ monocytes and cardiovascular outcome in patients with chronic kidney disease.

AIMS: Patients with chronic kidney disease (CKD) pose a worldwide growing burden to health care systems due to accelerated atherosclerosis and subsequent high cardiovascular (CV) morbidity. Atherogenesis is prominently driven by monocytes and monocyte-derived macrophages. The expression of CD14 and CD16 characterizes three monocyte subsets: CD14(++)CD16(-), CD14(++)CD16(+), and CD14((+))CD16(+) cells; the latter two are often denoted as 'proinflammatory' CD16(+) monocytes. Despite an association between CD16(+) monocyte counts and higher CV risk in cross-sectional cohorts, the prognostic impact of elevated CD16(+) monocyte counts is poorly understood. METHODS AND RESULTS: We assessed monocyte heterogeneity using flow cytometry in 119 patients with non-dialysis CKD, who were prospectively followed for a median of 4.9 (inter-quartile range 4.8-5.0) years for the occurrence of CV events. In addition, we assessed expression of chemokine receptors on monocyte subsets. CD14(++)CD16(+) monocyte were independently associated with CV events [hazard ratio (for an increase of 10 cells/µL) 1.26 (confidence interval: 1.04-1.52; P = 0.018)] after adjustment for variables that significantly affected CD14(++)CD16(+) cell counts at baseline. Across the spectrum of CKD, CD14(++)CD16(+) monocytes selectively expressed CCR5. CONCLUSION: We found that CD14(++)CD16(+) monocytes were independently associated with CV events in non-dialysis CKD patients. Our results support the notion that CD16(+) monocytes rather than CD16(-) monocytes are involved in human atherosclerosis.

The phosphatonin fibroblast growth factor 23 links calcium-phosphate metabolism with left-ventricular dysfunction and atrial fibrillation.

AIMS: High serum phosphate is linked to cardiovascular morbidity and mortality in the general population. Fibroblast growth factor 23 (FGF-23) is a critical phosphate regulating hormone, potentially reflecting phosphate load better than a single serum phosphate measurement. Recent pioneering echocardiographic studies associated FGF-23 with left-ventricular morphology. However, the association between FGF-23 and left-ventricular function is unknown, prompting us to investigate this relationship in our HOM SWEET HOMe study. METHODS AND RESULTS: We studied the association between C-terminal FGF-23, coronary artery disease, and left-ventricular function in 885 subjects undergoing elective coronary angiography. Left-ventricular function was assessed with ventriculography. More, pro-brain natriuretic peptide (pro-BNP) plasma levels were measured. The presence of left-ventricular hypertrophy and atrial fibrillation was assessed by electrocardiography. Patients with an ejection fraction <40% had significantly higher FGF-23 levels compared with patients with the ejection fraction >40% (P< 0.001). In multivariable regression analysis, the observed relationship between FGF-23 and left-ventricular function remained significant after adjustment for estimated glomerular filtration rate, presence of left-ventricular hypertrophy, and other confounding variables. In accordance, FGF-23 significantly correlated with pro-BNP plasma levels (r = 0.31; P< 0.001). Prevalent atrial fibrillation was associated with elevated FGF-23 levels, while the presence of coronary artery disease was not. CONCLUSIONS: Fibroblast growth factor 23 levels are associated with left-ventricular function and atrial fibrillation even in the absence of renal function impairment. Of note, these cross-sectional data cannot prove causality; therefore, future studies will have to discern whether FGF-23 exerts a direct untoward effect on the myocardium, or rather represents an 'innocent bystander' which reflects a high phosphate burden.

Plasma biomarkers outperform echocardiographic measurements for cardiovascular risk prediction in kidney transplant recipients: results of the HOME ALONE study.

Background: Since kidney transplant recipients (KTRs) have a high cardiovascular disease burden, adequate risk prediction is of importance. Whether echocardiographic parameters and plasma biomarkers, natriuretic peptides [N-terminal pro-B-type natriuretic peptide (NT-proBNP)] and troponin T provide complementary or overlapping prognostic information on cardiovascular events remains uncertain. Methods: The prospective Heterogeneity of Monocytes and Echocardiography Among Allograft Recipients in Nephrology (HOME ALONE) study followed 177 KTRs for 5.4 ± 1.7 years. Predefined endpoints were hospitalization for acute decompensated heart failure or all-cause death (HF/D) and major atherosclerotic cardiovascular events or all-cause death (MACE/D). At baseline, plasma NT-proBNP, plasma troponin T and echocardiographic parameters [left atrial volume index, left ventricular (LV) mass index, LV ejection fraction, and LV filling pressure] were assessed. Results: Among all echocardiographic and plasma biomarkers measured, only NT-proBNP was consistently associated with HF/D in univariate and multivariate {third versus first tertile: hazard ratio [HR] 4.20 [95% confidence interval (CI) 1.02-17.27]} analysis, and only troponin T was consistently associated with MACE/D in univariate and multivariate [third versus first tertile: HR 8.15 (95% CI 2.75-24.18)] analysis. Conclusion: Our data suggest that plasma biomarkers are robust and independent predictors of heart failure and atherosclerotic cardiovascular events after kidney transplantation, whereas standard echocardiographic follow-up does not add to risk prediction.

Monocyte heterogeneity in obesity and subclinical atherosclerosis.

AIMS: Monocytes and monocyte-derived macrophages have been recognised as the cellular hallmark of atherosclerosis decades ago. Recently, they have also been shown to play a pivotal role in obesity. Monocytes display immunophenotypic heterogeneity with functionally distinct subpopulations. We initiated the I LIKE HOMe study to examine monocyte heterogeneity in obesity and subclinical atherosclerosis. METHODS AND RESULTS: We assessed carotid intima media thickness (IMT), body mass index (BMI), and other cardiovascular risk factors in 622 healthy volunteers. Using flow-cytometry, we differentiated monocytes into CD14(++)CD16(-) and CD16(+) cells, which we further subdivided into CD14(++)CD16(+) and CD14((+))CD16(+) cells. Body mass index was significantly correlated with carotid IMT. High CD16(+) monocyte counts were significantly associated with both higher BMI and increased carotid IMT. Adjustment for CD16(+) monocyte counts weakened the correlation between BMI and carotid IMT, suggesting that the increase in CD16(+) monocyte numbers in obesity may partly explain the association between obesity and IMT. CONCLUSION: Our results reveal a significant univariate association between CD16(+) monocytes and both obesity and subclinical atherosclerosis in low-risk individuals. They are in line with recent observations that CD16(+) monocytes show high endothelial affinity and a potent capacity to invade vascular lesions and to transform into pro-inflammatory cytokine producing macrophages.

Markers of cholesterol synthesis to cholesterol absorption across the spectrum of non-dialysis CKD: An observational study.

In dialysis patients, cholesterol-lowering therapy with statins is less effective than in other high-risk patients. This may be explained by a shift from cholesterol synthesis toward cholesterol absorption. In line, markers of cholesterol absorption-such as campesterol-better predict atherosclerotic cardiovascular events than markers of cholesterol synthesis-such as lathosterol-in dialysis patients. To test the association between markers of cholesterol absorption such as campesterol-and markers of cholesterol synthesis-such as lathosterol-against cardiovascular events in non-dialysis CKD patients. Altogether 251 patients those not on lipid-lowering agents were followed annually for the composite endpoint atherosclerotic cardiovascular disease (ASCVD) and all-cause death. During follow-up of 5.2 ± 2.1 years, 61 participants reached the primary endpoint atherosclerotic cardiovascular disease/all-cause death [ASCVD/D], 47 participants suffered from ASCVD, and 46 participants died. In univariate Cox regression analysis, campesterol/lathosterol ratio did not significantly predict ASCVD/D (HR 0.643; 0.358-1.155; 3rd vs. 1st tertile), all-cause death (HR 1.309; 0.604-2.838; 3rd vs. 1st tertile) nor ASCVD (HR 0.589; 0.311-1.118; 3rd vs. 1st tertile). We did not observe a shift from cholesterol synthesis to cholesterol absorption across the spectrum of non-dialysis CKD. Campesterol/lathosterol ratio did not predict future ASCVD or all-cause death in non-dialysis CKD.

Indices of systemic atherosclerosis are superior to ultrasound resistance indices for prediction of allograft survival.

BACKGROUND: In renal allograft recipients, ultrasound resistance indices (RI) have been discussed as predictors of transplant survival. RI measurements are correlated with subclinical atherosclerosis. It is thus unclear whether RI measurements represent specific markers of allograft damage or merely reflect systemic vascular damage. We studied whether RI are superior outcome predictors compared to markers of subclinical atherosclerosis and global cardiovascular risk. METHODS: In 105 renal transplant patients, intrarenal RI and common carotid intima-media thickness (IMT) were measured. Risk for coronary heart disease was determined by Framingham risk scoring (FRS). Patients were followed up for 5.4 +/- 0.4 years. The combined end point was a decrease of > or =50% in estimated glomerular filtration rate, need for dialysis or death. RESULTS: Both an increased IMT and a high FRS were predictors of the combined end point. In contrast, increased RI did not significantly predict the combined end point in the entire cohort. Only among low-risk patients with either normal IMT or FRS < or =20%, high RI measurements were associated with allograft loss. CONCLUSIONS: Compared to markers of cardiovascular risk or systemic atherosclerosis, renal RI are inferior outcome predictors in unselected transplant recipients. Only in patients with mild or moderate cardiovascular risk may RI measurements allow additional risk stratification.

[Lipid management 2020 - medical therapy and lipid apheresis in context]. / Lipid-Management 2020 ­ medikamentöse Therapie und Lipidapherese im Kontext.

The recently updated 2019 European Society of Cardiology/European Atherosclerosis Society Guidelines for the management of dyslipidaemias set new, ambitious goals for lipid lowering based on recently generated evidence from large outcome trials. Noninvasive imaging as well as measurement of lipoprotein(a) as a non-traditional risk factor is advocated for the refinement of risk stratification. A highly potent statin - defined as a drug that lowers LDL-cholesterol by 50 % from baseline - is recommended as the standard choice of treatment, whenever medical lipid lowering is indicated. Combining different therapeutic strategies such as a statin with ezetimibe and/or a Proproteinkonvertase Subtilisin Kexin Type 9 inhibitor allows to achieve the new treatment targets. If needed, lipid apheresis can complement the medical armamentarium. Moreover, lipid apheresis remains the only approved treatment modality for lowering lipoprotein(a), however medical treatments are under current investigation.

Lipid-modifying therapy in chronic kidney disease: Pathophysiological and clinical considerations.

Chronic kidney disease (CKD), which affects >10% of the population worldwide, is associated with a dramatically increased rate of cardiovascular disease (CVD). More people with CKD will die from CVD than develop end-stage renal disease with dialysis-dependency. However, the contribution of classical atherosclerotic cardiovascular risk factors is less evident than in the general population. Particularly, the relationship between dyslipidemia and CVD morbidity and mortality in CKD patients is not as evident as in the general population. While LDL cholesterol-lowering drugs such as statins significantly reduce the rate of cardiovascular events in the general population, their role in patients with end-stage renal disease has been questioned. This could be caused by a shift from atherosclerotic to non-atherosclerotic CVD in patients with advanced CKD, which cannot be effectively prevented by lipid-lowering drugs. In addition, many lines of evidence suggest that impaired renal function directly affects the metabolism, composition and functionality of lipoproteins, which may affect their responsiveness to pharmacological interventions. In this review, we highlight the challenges for the therapeutic application of lipid-lowering treatment strategies in CKD and discuss why treatment strategies used in the general population cannot be applied uncritically to CKD patients.